Effect of Vagus Nerve Stimulation on the GASH/Sal Audiogenic-Seizure-Prone Hamster.

Vagus nerve stimulation (VNS) is an adjuvant neuromodulation therapy for the treatment of refractory epilepsy. However, the mechanisms behind its effectiveness are not fully understood. Our aim was to develop a VNS protocol for the Genetic Audiogenic Seizure Hamster from Salamanca (GASH/Sal) in order to evaluate the mechanisms of action of the therapy. The rodents were subject to VNS for 14 days using clinical stimulation parameters by implanting a clinically available neurostimulation device or our own prototype for laboratory animals. The neuroethological assessment of seizures and general behavior were performed before surgery, and after 7, 10, and 14 days of VNS. Moreover, potential side effects were examined. Finally, the expression of 23 inflammatory markers in plasma and the left-brain hemisphere was evaluated. VNS significantly reduced seizure severity in GASH/Sal without side effects. No differences were observed between the neurostimulation devices. GASH/Sal treated with VNS showed statistically significant reduced levels of interleukin IL-1ß, monocyte chemoattractant protein MCP-1, matrix metalloproteinases (MMP-2, MMP-3), and tumor necrosis factor TNF-α in the brain. The described experimental design allows for the study of VNS effects and mechanisms of action using an implantable device. This was achieved in a model of convulsive seizures in which VNS is effective and shows an anti-inflammatory effect.

Molecular tools for the characterization of seizure susceptibility in genetic rodent models of epilepsy.

Epilepsy is a chronic neurological disorder characterized by abnormal neuronal activity that arises from imbalances between excitatory and inhibitory synapses, which are highly correlated to functional and structural changes in specific brain regions. The difference between the normal and the epileptic brain may harbor genetic alterations, gene expression changes, and/or protein alterations in the epileptogenic nucleus. It is becoming increasingly clear that such differences contribute to the development of distinct epilepsy phenotypes. The current major challenges in epilepsy research include understanding the disease progression and clarifying epilepsy classifications by searching for novel molecular biomarkers. Thus, the application of molecular techniques to carry out comprehensive studies at deoxyribonucleic acid, messenger ribonucleic acid, and protein levels is of utmost importance to elucidate molecular dysregulations in the epileptic brain. The present review focused on the great diversity of technical approaches available and new research methodology, which are already being used to study molecular alterations underlying epilepsy. We have grouped the different techniques according to each step in the flow of information from DNA to RNA to proteins, and illustrated with specific examples in animal models of epilepsy, some of which are our own. Separately and collectively, the genomic and proteomic techniques, each with its own strengths and limitations, provide valuable information on molecular mechanisms underlying seizure susceptibility and regulation of neuronal excitability. Determining the molecular differences between genetic rodent models of epilepsy and their wild-type counterparts might be a key in determining mechanisms of seizure susceptibility and epileptogenesis as well as the discovery and development of novel antiepileptic agents. This article is part of the Special Issue "NEWroscience 2018".

Process evaluation of a complex workplace intervention to prevent musculoskeletal pain in nursing staff: results from INTEVAL_Spain.

BACKGROUND: INTEVAL_Spain was a complex workplace intervention to prevent and manage musculoskeletal pain among nursing staff. Process evaluations can be especially useful for complex and multifaceted interventions through identifying the success or failure factors of an intervention to improve the intervention implementation. OBJECTIVES: This study performed a process evaluation of INTEVAL_Spain and aimed to examine whether the intervention was conducted according to the protocol, to investigate the fulfilment of expectations and the satisfaction of workers. METHODS: The intervention was a two-armed cluster randomized controlled trial and lasted 1 year. The process evaluation included quantitative and qualitative methods. Quantitative methods were used to address the indicators of Steckler and Linnan's framework. Data on recruitment was collected through a baseline questionnaire for the intervention and the control group. Reach and dose received were collected through participation sheets, dose delivered and fidelity through internal registries, and fulfilment of expectations and satisfaction were collected with two questions at 12-months follow-up. Qualitative methods were used for a content analysis of discussion groups at the end of the intervention led by an external moderator to explore satisfaction and recommendations. The general communication and activities were discussed, and final recommendations were agreed on. Data were synthesized and results were reported thematically. RESULTS: The study was performed in two Spanish hospitals during 2016-2017 and 257 workers participated. Recruitment was 62 and 51% for the intervention and the control group, respectively. The reach of the activities ranged from 96% for participatory ergonomics to 5% for healthy diet. The number of sessions offered ranged from 60 sessions for Nordic walking to one session for healthy diet. Fidelity of workers ranged from 100% for healthy diet and 79% for participatory ergonomics, to 42 and 39% for Nordic walking and case management, respectively. Lowest fidelity of providers was 75% for case management and 82% for Nordic walking. Fulfilment of expectations and satisfaction ranged from 6.6/10 and 7.6/10, respectively, for case management to 10/10 together for the healthy diet session. Discussion groups revealed several limitations for most of the activities, mainly focused on a lack of communication between the Champion (coordinator) and the workers. CONCLUSIONS: This process evaluation showed that the implementation of INTEVAL_Spain was predominantly carried out as intended. Process indicators differed depending on the activity. Several recommendations to improve the intervention implementation process are proposed. TRIAL REGISTRATION: ISRCTN15780649 .

Associations between sensorimotor gating mechanisms and athletic performance in a variety of physical conditioning tests.

PURPOSE: The elite athlete is fine-tuned all around to deliver favorable results in sporting events. In this study, we address the question of whether basic movements-such as reflexes-and heterogeneous attentional modulation components-such as sensorimotor gating mechanisms-are also tuned up to maximize the results of middle-distance runners in physical conditioning tests. METHODS: We selected an array of professional middle-distance runners and healthy counterparts that were submitted to measurement of (1) physical conditioning parameters, including somatotype, jump, strength, and flexibility tests; and (2) sensorimotor gating mechanisms, including acoustic startle reflex, prepulse inhibition, and habituation. RESULTS: Our results showed athletes scored better on the athletic tests compared to controls, as expected. They also exhibited a lower startle amplitude, while maintaining higher prepulse inhibition values. They reacted faster to the acoustic stimuli, and sex-related differences-found in controls-were not present in athletes. Our data also pointed out to substantial correlations between sensorimotor gating and physical conditioning parameters. CONCLUSIONS: All in all, these data may point to physical conditioning-driven neural plasticity of brain sensorimotor gating circuits in charge of triggering involuntary movements to harness control and efficiency over reflexed muscle activity.

Assessing the Effectiveness of Eslicarbazepine Acetate in Reducing Audiogenic Reflex Seizures in the GASH/Sal Model of Epilepsy.

Eslicarbazepine acetate (ESL) is a third-generation antiepileptic drug indicated as monotherapy for adults with newly diagnosed epilepsy and as adjunctive therapy for the treatment of partial seizures. Our aim was to assess the effectiveness and safety of both acute and repeated ESL administration against reflex audiogenic seizures, as shown by the Genetic Audiogenic Seizures Hamster from Salamanca (GASH/Sal). Animals were subject to the intraperitoneal administration of ESL, applying doses of 100, 150 and 200 mg/kg for the acute study, whereas a daily dose of 100 mg/kg was selected for the subchronic study, which lasted 14 days. In both studies, the anticonvulsant effect of the therapy was evaluated using neuroethological methods. To assess the safety of the treatment, behavioral tests were performed, hematological and biochemical liver profiles were obtained, and body weight was monitored. In addition, the ESL levels in blood were measured after the acute administration of a 200 mg/kg dose. Treatment with ESL caused a reduction in seizure severity. No statistically significant differences were detected between the selected doses or between the acute or repeated administration of the drug. To summarize, the intraperitoneal administration of ESL is safe and shows an anticonvulsant effect in the GASH/Sal.

Implementation of a virtual community of practice to promote the empowerment of middle-aged people with multimorbidity: study protocol of a randomised controlled trial.

INTRODUCTION: Empowering people living with multimorbidity (multiple chronic conditions) to gain greater confidence in managing their health can enhance their quality of life. Education focused on self-management is a key tool for fostering patient empowerment and is mostly provided on an individual basis. Virtual communities of practice (VCoP) present a unique opportunity for online education in chronic condition self-management within a social context. This research aims to evaluate the effectiveness/cost-effectiveness of individualised, online self-management education compared with VCoP among middle-aged individuals living with multiple chronic conditions. METHODS AND ANALYSIS: People aged 30-60, living with ≥2 chronic conditions and receiving care in primary care (PC) centres and outpatient hospital-based clinics in Madrid and Canary Islands will enrol in an 18-month parallel-design, blinded (intervention assessment and data analysts), pragmatic (adhering to the intention-to-treat principle), individually randomised trial. The trial will compare two 12-month web-based educational offers of identical content; one delivered individually (control) and the other with online social interaction (VCoP, intervention). Using repeated measures mixed linear models, with the patient as random effect and allocation groups and time per group as fixed effects, we will estimate between-arm differences in the change in Patient Activation Measure from baseline to 12 months (primary endpoint), including measurements at 6-month and 18-month follow-up. Other outcomes will include measures of depression and anxiety, treatment burden, quality of life. In addition to a process evaluation of the VCoP, we will conduct an economic evaluation estimating the relative cost-effectiveness of the VCoP from the perspectives of both the National Health System and the Community. ETHICS AND DISSEMINATION: The trial was approved by Clinical Research Ethics Committees of Gregorio Marañón University Hospital in Madrid/Nuestra Señora Candelaria University Hospital in Santa Cruz de Tenerife. The results will be disseminated through workshops, policy briefs, peer-reviewed publications and local/international conferences. TRIAL REGISTRATION NUMBER: NCT06046326.

No association between prepulse inhibition of the startle reflex and neuropsychological deficit in chronic schizophrenia.

Sensorimotor gating deficits are relevant in schizophrenia and can be measured using prepulse inhibition (PPI) of the startle reflex. It is conceivable that such deficits may hinder the cognitive functions in schizophrenia patients. In this study, using PPI and a neuropsychological battery, we studied this possibility in a group of 23 acute, neuroleptic-free schizophrenia patients and 16 controls. A non-significant decrease in PPI was found in the patients as compared to the controls, as well as significant differences in the performance of Trail A and B in Wisconsin Card Sorting and Digit/Symbol Tests. No statistically significant correlations between PPI and neuropsychological performance were found after the correction for multiple comparisons in any group. Our results suggest that PPI deficits in schizophrenia patients may not contribute to the cognitive deficits typical of that illness, at least in patients with a non-significant PPI decrease.

Design of an interface for teaching cardiovascular physiology to anesthesia clinicians with a patient simulator connected to a minimally invasive cardiac output monitor (LiDCO rapid®).

Cardiovascular physiology can be simulated in patient simulators but is limited to the simulator monitor curves and parameters, missing some important data that today is known as essential to fluid management and therapeutic decision in critical ill and high-risk surgical patients. Our main objective was to project and implement a unidirectional communication channel between a pre-existing patient simulator and a minimally invasive cardiac output monitor (LiDCO rapid®); a monitor that connects to real patients and interprets the arterial wave. To connect the patient simulator to the hemodynamic monitor, firstly, we had to assess both systems and design a communication channel between them. LiDCO monitor accepts as an input an analog voltage varying between 0 V and 5 V and that every volt is directly proportional to a blood pressure (mmHg) value ranging from 0 mmHg (0 V) to 500 mmHg (5 V). A Raspberry Pi 0 (Rpi0) with a WIFI chip integrated was needed and added to a digital analogue converter connected to the board. We designed a system that allowed us to collect, interpret and modify data, and feed it to the LiDCO rapid® monitor. We had developed a Python® script with three independent threads and a circular buffer to handle the data transmission between both systems. The LiDCO hemodynamic monitor successfully received data sent from our setup like a real patient arterial wave pulse and interpreted it to estimate several hemodynamic parameters, as cardiac output, stroke volume, systemic vascular resistance, pulse pressure variation, and stroke volume variation. The connection between the patient simulator and the LiDCO monitor is being used to create arterial curves and other hemodynamic parameters for clinical scenarios where residents and anesthesiologists can simulate a variety of unstable hemodynamic conditions, preparing them to face similar situations with real patients in a safe environment and with their own monitors.

Propofol TCI Reductions Do Not Attenuate Significant Falls in Cardiac Output Associated With Anesthesia Induction and Knee-Chest Positioning in Spinal Surgery.

BACKGROUND: Induction of anesthesia and the knee-chest position are associated with hemodynamic changes that may impact patient outcomes. The aim of this study was to assess whether planned reductions in target-controlled infusion propofol concentrations attenuate the hemodynamic changes associated with anesthesia induction and knee-chest position. MATERILAS AND METHODS: A total of 20 patients scheduled for elective lumbar spinal surgery in the knee-chest position were included. In addition to standard anesthesia monitoring, bispectral index and noninvasive cardiac output (CO) monitoring were undertaken. The study was carried out in 2 parts. In phase 1, target-controlled infusion propofol anesthesia was adjusted to maintain BIS 40 to 60. In phase 2, there were 2 planned reductions in propofol target concentration: (1) immediately after loss of consciousness-reduction calculated using a predefined formula, and (2) before positioning-reduction equal to the average percentage decrease in CO after knee-chest position in phase 1. Changes from baseline in CO and other hemodynamic variables following induction of anesthesia and knee-chest positioning were compared. RESULTS: Induction of anesthesia led to decreases of 25.6% and 19.8% in CO from baseline in phases 1 and 2, respectively (P<0.01). Knee-chest positioning resulted in a further decrease such that the total in CO reduction from baseline to 10 minutes after positioning was 38.4% and 46.9% in phases 1 and 2, respectively (P<0.01). There was no difference in CO changes between phases 1 and 2, despite the planned reductions in propofol during phase 2. There was no significant correlation between changes in CO and mean arterial pressure. CONCLUSIONS: Planned reductions in propofol concentration do not attenuate anesthesia induction and knee-chest position-related decreases in CO. The knee-chest position is an independent risk factor for decrease in CO. Minimally invasive CO monitors may aid in the detection of clinically relevant hemodynamic changes and guide management in anesthetized patients in the knee-chest position.

Behavioral and Molecular Effects Induced by Cannabidiol and Valproate Administration in the GASH/Sal Model of Acute Audiogenic Seizures.

Despite evidence that supports cannabidiol (CBD) as an anticonvulsant agent, there remains controversy over the antiseizure efficacy, possible adverse effects, and synergistic interactions with classic antiepileptics such as valproate (VPA). The genetic audiogenic seizure hamster from the University of Salamanca (GASH/Sal) is a reliable experimental model of generalized tonic-clonic seizures in response to intense sound stimulation. The present study examines the behavioral and molecular effects of acute and chronic intraperitoneal administrations of VPA (300 mg/kg) and CBD (100 mg/kg) on the GASH/Sal audiogenic seizures, as well as the coadministration of both drugs. The GASH/Sal animals were examined prior to and after the corresponding treatment at 45 min, 7 days, and 14 days for seizure severity and neuroethology, open-field behaviors, body weight variations, and various hematological and biochemical parameters. Furthermore, the brain tissue containing the inferior colliculus (so-called epileptogenic nucleus) was processed for reverse transcription-quantitative polymerase chain reaction analysis to determine the treatment effects on the gene expression of neuronal receptors associated with drug actions and ictogenesis. Our results indicated that single dose of VPA helps prevent the animals from getting convulsions, showing complete elimination of seizures, whereas 7 days of chronic VPA treatment had few effects in seizure behaviors. Acute CBD administration showed subtle attenuation of seizure behaviors, increasing seizure latency and decreasing the duration of the convulsion phase, but without entirely seizure abolition. Chronic CBD treatments had no significant effects on sound-induced seizures, although some animals slightly improved seizure severity. Acute and chronic CBD treatments have no significant adverse effects on body weight, hematological parameters, and liver function, although locomotor activity was reduced. The combination of VPA and CBD did not alter the therapeutic outcome of the VPA monotherapy, showing no apparent synergistic effects. As compared to sham animals, chronic treatments with CBD caused abnormal mRNA expression levels for Trpv1, Adora1, Slc29a1, and Cnr1 genes, whereas no differences in gene expression were found for Htr1a and Sigmar1. Our study shed light on the behavioral and molecular effects of CBD and VPA on the GASH/Sal model and constituted the basis to develop further studies on the pharmacological effects of CBD and its interactions with other anticonvulsants.

SFCE-RAPIRI Phase I Study of Rapamycin Plus Irinotecan: A New Way to Target Intra-Tumor Hypoxia in Pediatric Refractory Cancers.

Hypoxic environment is a prognostic factor linked in pediatric cancers to a worse outcome, favoring tumor progression and resistance to treatments. The activation of mechanistic Target Of Rapamycin (mTor)/hypoxia inducible factor (HIF)-1 pathway can be targeted by rapamycin and irinotecan, respectively. Therefore, we designed a phase I trial associating both drugs in pediatric refractory/relapsing solid tumors. Patients were enrolled according to a 3 + 3 escalation design with ten levels, aiming to determine the MTD (maximum tolerated dose) of rapamycin plus irinotecan. Rapamycin was administered orally once daily in a 28-day cycle (1 to 2.5 mg/m2/day), associating biweekly intravenous irinotecan (125 to 240 mg/m2/dose). Toxicities, pharmacokinetics, efficacy analyses, and pharmacodynamics were evaluated. Forty-two patients, aged from 2 to 18 years, were included. No MTD was reached. Adverse events were mild to moderate. Only rapamycin doses of 1.5 mg/m2/day reached over time clinically active plasma concentrations. Tumor responses and prolonged stable disease were associated with a mean irinotecan area under the curve of more than 400 min.mg/L. Fourteen out of 31 (45.1%) patients had a non-progressive disease at 8 weeks. Most of them were sarcomas and brain tumors. For the phase II trial, we can then propose biweekly 125 mg/m2 irinotecan dose with a pharmacokinetic (PK) follow-up and a rapamycin dose of 1.5 mg/m2/day, reaching a blood concentration above 10 g/L.

Effect of Hemodynamic Changes in Plasma Propofol Concentrations Associated with Knee-Chest Position in Spinal Surgery: A Prospective Study.

BACKGROUND: Anesthesia induction and maintenance with propofol can be guided by target-controlled infusion (TCI) systems using pharmacokinetic (Pk) models. Physiological variables, such as changes in cardiac output (CO), can influence propofol pharmacokinetics. Knee-chest (KC) surgical positioning can result in CO changes. OBJECTIVES: This study aimed to evaluate the relationship between propofol plasma concentration prediction and CO changes after induction and KC positioning. METHODS: This two-phase prospective cohort study included 20 patients scheduled for spinal surgery. Two different TCI anesthesia protocols were administered after induction. In phase I (n = 9), the loss of consciousness (LOC) concentration was set as the propofol target concentration and CO changes following induction and KC positioning were quantified. In phase II (n = 11), based on data from phase I, two reductions in the propofol target concentration on the pump were applied after LOC and before KC positioning. Propofol plasma concentrations were measured at different moments in both phases: after induction and after KC positioning. RESULTS: Schnider Pk model showed a good performance in predicting propofol concentration after induction; however, after KC positioning, when a significant drop in CO occurred, the measured propofol concentrations were markedly underestimated. Intended reductions in the propofol target concentration did not attenuate HD changes. In the KC position, there was no correlation between the propofol concentration estimated by the Pk model and the measured concentration in plasma, as the latter was much higher (P = 0.013) while CO and BIS decreased significantly (P < 0.001 and P = 0.004, respectively). CONCLUSIONS: Our study showed that the measured propofol plasma concentrations during the KC position were significantly underestimated by the Schnider Pk model and were associated with significant CO decrease. When placing patients in the KC position, anesthesiologists must be aware of pharmacokinetic changes and, in addition to standard monitoring, the use of depth of anesthesia and cardiac output monitors may be considered in high-risk patients.

Relations between Sensorimotor Integration and Speech Disorders in Parkinson's Disease.

BACKGROUND: Sensorimotor integration mechanisms can be affected by many factors, among which are those involving neuromuscular disorders. Parkinson's disease (PD) is characterized by well-known motor symptoms, among which lately have been included motor speech deficits. Measurement of the acoustic startle reflex (ASR) and its modulations (prepulse inhibition and prepulse facilitation, PPI and PPF respectively) represent a simple and quantifiable tool to assess sensorimotor function. However, it remains unknown whether measures of the PPI and PPF are associated with motor speech deficits in PD. METHODS: A total of 88 subjects participated in this study, 52 diagnosed with PD and 36 control subjects. After obtaining written informed consent, participants were assessed with PPI at several interstimulus intervals, and PPF at 1000 ms using the SRH-Lab system (San Diego, CA). Percentage of change in the amplitude and latency of the ASR was analyzed between groups. Voice recordings were register of a specific text given to the subjects with a professional recorder and temporal patterns of speech were analyzed. RESULTS: Statistical analysis conducted in this study showed differences in PPI and PPF in subjects with PD compared to controls. In addition, discriminative parameters of voice abnormalities were observed in PD subjects related to control subjects showing a reduction in phonation time, vowel pulses, breaks, breakage and voice speech periods. CONCLUSIONS: PD presents a disruption in sensorimotor filter mechanisms and speech disorders, and there is a relationship between these alterations. The correlation between the PPI and PPF with an alteration of the voice in PD subjects contributes toward understanding mechanism underlying the neurophysiological alterations in both processes. Overall, easy and non-invasive tests such as PPI, PPF together with voice analysis may be useful to identify early stages of PD.

Long-Term Sertraline Intake Reverses the Behavioral Changes Induced by Prenatal Stress in Rats in a Sex-Dependent Way.

Early life stress is a major factor underlying the vulnerability to respond to stressful events later in life. The present study attempted to evaluate the role of prenatal stress affecting the development of stress-related disorders and their reversion by postnatal exposure to Sertraline (SERT), a front-line medication for medication for posttraumatic stress disorder (PTSD) in humans. To achieve this, adult male and female prenatally stressed (PS) or unstressed (Controls) offspring rats, following oral chronic treatment with SERT (5 mg/kg/day; from 1 month to 4 months old), or not, were studied prior to and after a traumatic event. First, anxiety-like behavior during the prepulse inhibition (PPI) test, a modulation of the startle reflex, was examined in all animals. Subsequently, the animals were subjected to a session of mild inescapable footshocks (IS; 0.35 mA, 5 s) in a shuttle box that was followed by 4 days of situational reminders in the aversive context. Prior to the footshocks no effects of PS or SERT were shown, and no changes in PPI and the habituation to the shuttle box were found. After them, PS led animals to exhibit behavioral alterations. When compared to the Controls, PS animals of both sexes displayed less rearing activity in the aversive environment. PS males responded less to footshock delivery and, in most of the animals, fear extinction was impaired. Moreover, the early postnatal exposure to SERT lessened the behavioral impact of PS in females, while in males it had no effect. Current results extend previous data from our laboratory, showing that PS heightened vulnerability to stress later on, and that SERT acts differently in males and females.

Morphological correlates of sex differences in acoustic startle response and prepulse inhibition through projections from locus coeruleus to cochlear root neurons.

The noradrenergic locus coeruleus (LC) plays an important role in the promotion and maintenance of arousal and alertness. Our group recently described coerulean projections to cochlear root neurons (CRNs), the first relay of the primary acoustic startle reflex (ASR) circuit. However, the role of the LC in the ASR and its modulation, prepulse inhibition (PPI), is not clear. In this study, we damaged LC neurons and fibers using a highly selective neurotoxin, DSP-4, and then assessed ASR and PPI in male and female rats. Our results showed that ASR amplitude was higher in males at 14 days after DSP-4 injection when compared to pre-administration values and those in the male control group. Such modifications in ASR amplitude did not occur in DSP-4-injected females, which exhibited ASR amplitude within the range of control values. PPI differences between males and females seen in controls were not observed in DSP-4-injected rats for any interstimulus interval tested. DSP-4 injection did not affect ASR and PPI latencies in either the male or the female groups, showing values that were consistent with the sex-related variability observed in control rats. Furthermore, we studied the noradrenergic receptor system in the cochlear nerve root using gene expression analysis. When compared to controls, DSP-4-injected males showed higher levels of expression in all adrenoceptor subtypes; however, DSP-4-injected females showed varied effects depending on the receptor type, with either up-, downregulations, or maintenance of expression levels. Lastly, we determined noradrenaline levels in CRNs and other LC-targeted areas using HPLC assays, and these results correlated with behavioral and adrenoceptor expression changes post DSP-4 injection. Our study supports the participation of LC in ASR and PPI, and contributes toward a better understanding of sex-related differences observed in somatosensory gating paradigms.

Mutations in signal recognition particle SRP54 cause syndromic neutropenia with Shwachman-Diamond-like features.

Shwachman-Diamond syndrome (SDS) (OMIM #260400) is a rare inherited bone marrow failure syndrome (IBMFS) that is primarily characterized by neutropenia and exocrine pancreatic insufficiency. Seventy-five to ninety percent of patients have compound heterozygous loss-of-function mutations in the Shwachman-Bodian-Diamond syndrome (sbds) gene. Using trio whole-exome sequencing (WES) in an sbds-negative SDS family and candidate gene sequencing in additional SBDS-negative SDS cases or molecularly undiagnosed IBMFS cases, we identified 3 independent patients, each of whom carried a de novo missense variant in srp54 (encoding signal recognition particle 54 kDa). These 3 patients shared congenital neutropenia linked with various other SDS phenotypes. 3D protein modeling revealed that the 3 variants affect highly conserved amino acids within the GTPase domain of the protein that are critical for GTP and receptor binding. Indeed, we observed that the GTPase activity of the mutated proteins was impaired. The level of SRP54 mRNA in the bone marrow was 3.6-fold lower in patients with SRP54-mutations than in healthy controls. Profound reductions in neutrophil counts and chemotaxis as well as a diminished exocrine pancreas size in a SRP54-knockdown zebrafish model faithfully recapitulated the human phenotype. In conclusion, autosomal dominant mutations in SRP54, a key member of the cotranslation protein-targeting pathway, lead to syndromic neutropenia with a Shwachman-Diamond-like phenotype.

Twenty years' experience for reduction of ileocolic intussusceptions by saline enema under sonography control.

BACKGROUND: Ultrasonography is a well-established efficient diagnostic tool for ileocolic intussusceptions in children. It can also be used to control hydrostatic reduction by saline enemas. This reduction method presents the advantage of avoiding radiations. Parents can even stay with their children during the procedure, which is comforting for both. The purpose of this study was to present our 20 years' experience in intussusception reductions using saline enema under ultrasound control and to assess its efficiency and safety. MATERIAL AND METHODS: This retrospective single center study included patients with ileocolic intussusceptions diagnosed by ultrasound between June 1993 and July 2013. We excluded the data of patients with spontaneous reduction or who underwent primary surgery because of contraindications to hydrostatic reduction (peritonitis, medium or huge abdominal effusion, ischemia on Doppler, bowel perforation). A saline enema was infused into the colon until the reduction was sonographically confirmed. The procedure was repeated if not efficient. Light sedation was practiced in some children. RESULTS: Eighty-tree percent of the reductions were successful with a median of 1 attempt. Reduction success decreased with the number of attempts but was still by 16% after 4 attempts. The early recurrence rates were 14.5%, and 61.2% of those had a successful second complete reduction. Forty-six patients needed surgery (11 of them had a secondary intussusception). Sedation multiplies success by 10. In this period, only one complication is described. CONCLUSION: Ultrasound guided intussusception reduction by saline enema is an efficient and safe procedure. It prevents exposure of a young child to a significant amount of radiation, with similar success rate. We had very low complication rate (1/270 cases or 3‰). The success rate could be increased by standardized procedures including: systematic sedation, trained radiologists, accurate pressure measurement, and number and duration of attempts.

The effects of sertraline administration from adolescence to adulthood on physiological and emotional development in prenatally stressed rats of both sexes.

Sertraline (SERT) is a clinically effective Selective Serotonin Reuptake Inhibitor (SSRI) known to increase and stabilize serotonin levels. This neurotransmitter plays an important role in adolescent brain development in both rodents and humans, and its dysregulation has been correlated with deficits in behavior and emotional regulation. Since prenatal stress may disturb serotoninergic homeostasis, the aim of this study was to examine the long-lasting effects of exposure to SERT throughout adolescence on behavioral and physiological developmental parameters in prenatally stressed Wistar rats. SERT was administered (5 mg/kg/day p.o.) from the age of 1-3 months to half of the progeny, of both sexes, of gestating dams stressed by use of a restraint (PS) or not stressed. Our data reveal that long-term SERT treatment slightly reduced weight gain in both sexes, but reversed the developmental disturbed "catch-up" growth found in PS females. Neither prenatal stress nor SERT treatment induced remarkable alterations in behavior and had no effects on mean startle reflex values. However, a sex-dependent effects of PS was found: in males the PS paradigm slightly increased anxiety-like behavior in the open field, while in females, it impaired startle habituation. In both cases, SERT treatment reversed the phenomena. Additionally, the PS animals exhibited a disturbed leukocyte profile in both sexes, which was reversed by SERT. The present findings are evidence that continuous SERT administration from adolescence through adulthood is safe in rodents and lessens the impact of prenatal stress in rats.

EEG characterization of audiogenic seizures in the hamster strain GASH:Sal.

The study was performed to characterize GASH:SAL audiogenic seizures as true epileptic activity based on electroencephalographic markers acquired with a wireless implanted radiotelemetry system. We analyzed cortical EEG patterns synchronized with video recordings of convulsive behavior of the GASH:Sal hamster following an acoustic stimulus. All GASH:Sal presented archetypal motor symptoms comparable to current animal models of generalized tonic-clonic epilepsy. Seizures consisted of an initial bout of wild running, followed by opisthotonus, tonic-clonic convulsions, tonic limb extension, and terminated in postictal depression. EEG patterns correlated with behavior and displayed phase appropriate spike-wave complexes, low-amplitude desynchronized activity, and high frequency large-amplitude peaks. Our results confirm that electroencephalographic profiles of the audiogenic seizures of the hamster GASH:Sal are parallel to EEG patterns of other animal models of generalized tonic-clonic seizures. Therefore, this animal may serve as an appropriate model for epilepsy research.